Research articles
ScienceAsia 50 (2024):ID 2024076 1-9 |doi:
10.2306/scienceasia1513-1874.2024.076
11β- hydroxysteroid dehydrogenase type 1 selective inhibitor
alleviates insulin resistance and non-alcoholic fatty liver
disease in db/db mice
Wen-wen Qia, Yong Liub, Peng-fei Liuc, Mei Yib, Chao Zhangb, Shuang Zhangd, Li-Yong Zhonga,*
ABSTRACT: Non-alcoholic fatty liver disease, often linked to insulin resistance, is associated with increased expression
of 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1) in liver tissue. We here assessed the effects of the 11?-HSD1
inhibitor BVT.2733 on non-alcoholic fatty liver disease and its underlying mechanisms. Mice were divided into three
groups: control, db/db, and db/db +BVT.2733. After 4 weeks, serological testing was conducted, and glucose tolerance
and insulin sensitivity were assessed. The severity of non-alcoholic fatty liver disease was evaluated using B-ultrasound,
Hematoxylin and Eosin staining, and Oil Red O staining. Liver corticosterone levels were measured using enzyme-linked
immunosorbent assay. Liver expression of 11?-HSD1, Phosphatidylinositol 3-kinase (PI3K) -Serine-Threonine kinase
(AKT)-Mammalian target of rapamycin (mTOR) signaling pathway-related proteins, and autophagy-related proteins
were analyzed by western blot. The results indicated that the leptin receptor-deficient mice db/db showed significant
glucolipid metabolism disorder, insulin resistance, and increased non-alcoholic fatty liver disease severity, compared
with the control group. BVT.2733 treatment ameliorated these conditions. Specifically, BVT.2733 downregulated liver
11?-HSD1 expression, resulting in reduced liver corticosterone levels. Additionally, BVT.2733 enhanced hepatocyte
autophagy, activated the PI3K-AKT signaling pathway and inhibited the mTOR signaling pathway. These findings
suggest that BVT.2733 not only improves glucolipid metabolism and insulin resistance but also mitigates non-alcoholic
fatty liver disease, in leptin receptor-deficient mice db/db. The underlying mechanism likely involves decreased liver
corticosterone levels and enhanced hepatocyte autophagy, mediated by the PI3K-AKT and mTOR signaling pathways.
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| a |
Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070 China |
| b |
Department of Ultrasound, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038 China |
| c |
Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038 China |
| d |
Department of Pathology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038 China |
* Corresponding author, E-mail: zhongliyong@bjtth.org
Received 27 May 2023, Accepted 6 Jul 2024
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